Malignant Hyperthermia Slides PDF

**Malignant Hyperthermia is when the Skeletal muscles contract excessively, producing heat and excessive C02 and tachycardia.** ------------------------------------------------------------------------------------------------------------------------------- **It is a life-threatening hyperthermic rea...

**Malignant Hyperthermia is when the Skeletal muscles contract excessively, producing heat and excessive C02 and tachycardia.** ------------------------------------------------------------------------------------------------------------------------------- **It is a life-threatening hyperthermic reaction to GA (Gases and Succinylcholine).** ------------------------------------------------------------------------------------- **Let's now learn how this all happens!!** ------------------------------------------ Normal skeletal muscle contraction ================================== Okay so far, we've been discussing the pattern before the neurotransmitter reaches partner receptor site and the effect of drugs at the receptor sites. But now we go further to discuss the ions involved after the neurotransmitter has entered the receptor. Think of: **Sodium (Na+):** The initiator ion which kickstarts Ca++ **Calcium (Ca++):** Main contraction (Squeeze) ion **Adenosine Triphosphate (ATP)**: eats ions for energy (Just like we eat a biscuit and have to run 2 miles to burn it off (energy burns something!)) So now: Let's think of normal skeletal muscle contraction 1. **Ca++** is a big player in the contraction of skeletal muscle, but it's not present in the cytoplasm (jelly part of the cell, where mitochondria and other bits float). It's stored in the **sarcoplasmic reticulum** (**SR**) in **muscle** cells (Remember: It is important to store a picture in your mind to consider fixing it into your memory: I like the one below). Think of it as intracellular (inside the cell) saclike membranes. The tubes are actually thread like and are tubular constructs of muscle cell (Imagine a muscle cell with tubes inside and covering these like a web are sarcoplasmic reticulum) 2. Skeletal muscle is stimulated for contraction by an electrical impulse arriving to the neuromuscular junction and the release of the neurotransmitter **acetylcholine (ACh).** 3. ACh crosses the synapse, binds to receptors found on the skeletal muscle, and depolarizes the skeletal muscle (Remember depolarisation is a transfer of + positive ions into cells) 4. It is the depolarization of the skeletal muscle that releases the stored Ca^++^ from the SR, resulting in muscular contraction. 5. **Ryanodine receptors (RyRs**) are huge ion channels that are responsible for the release of Ca(2+) from the SR (mediate the release of calcium ions)  6. But Calcium alone doesn't cause contraction. The key thing is that muscle contraction happens as a result of the interaction of the **actin and myosin** filaments, which slide over one another when they interact, leading to shortening of the muscle fibre (Think about Ca++ as a vibrator which causes the muscle fibres to rub against each other and constrict ). When something constricts it goes smaller in size! 7. Now at rest, this reaction is prevented by **troponin,** which mechanically stands between actin and myosin binding sites. Muscle Fiber Contraction and Relaxation · Anatomy and Physiology 8. So, when Ca++ is released from the SR, it binds with troponin, shifts it out of the way and lets myosin and actin interact allowing muscle fibre shortening. 9. In this whole process we use up ATP in **2 ways:** **Adenosine triphosphate (ATP),** (energy storage molecule used as a fuel for cellular work), is used up in 2 ways during skeletal muscle contraction. (1. Energy and heat released in the process of trying to stop the interaction of actin and myosin and 2. Energy and heat released while trying to actively pump Ca++ back into the SR) 10. Take exercise as an example: repetitive muscular contraction **depletes oxygen and ATP stores** and **increases in both local and systemic temperature and C02 output** (we hyperventilate to let it out) So now: What goes wrong in this process during malignant hyperthermia (pathophysiology: changes to normal physiology) ===================================================================================================================== 1. Some patients have the MH trait; genetically altered **ryanodine (RyR1)** receptor which release too much Ca++ and depletes ATP (only when exposed to volatile inhalation agents or succinylcholine (sux), and hence an abnormally heightened state of muscular contraction. 2. This excessive contraction of skeletal muscle leads to a sustained **hypermetabolic** state (remember metabolism is associated with heat) and significantly increases in the production of carbon dioxide (CO2) from the rapid utilization of ATP (which is working hard to push out the Ca++) 3. This leads to systemic hypoxemia, lactic acidosis, and the widespread damage and destruction of skeletal muscle cells and also **increases potassium (K+)** and **myoglobin** (iron and 02 binding protein which is usually only released in blood after muscle injury). 4. Increased production and elimination of CO2 may be seen in the end-tidal CO2 or the CO2 absorber canister of the anaesthesia machine. 5. A rapid decline in oxygen saturation and the appearance of cyanosis may be indicative of the increased utilization and requirements of oxygen. 6. The increased production of CO2 and utilization of oxygen is treated with the immediate elimination of volatile inhalation agents and the administration of 100% oxygen. 7. Tachycardia is seen as a result of the **hypermetabolic state** (when we use too much ATP for energy), and the development of ventricular extrasystoles may follow acidosis and the effects of extra K+ on the cardiac muscle.  8. Unregulated intracellular Ca++ triggers a quick onset **hypercatabolic** state (increased catabolic hormones, such as cytokines/cortisol/catecholamines) (These are released in bodily stress-they consume oxygen and burn fat as well). Symptoms include tachypnoea, tachycardia, hyperthermia, hyperkalaemia, muscle rigidity, myoglobinuria (Myoglobin in urine) 9. Several other conditions may mimic MH and must be eliminated first. These disorders include neurologic events such as intracranial trauma and hypoxic encephalitis (inflammation in brain from virus which stops enough 02 reaching brain); endocrine disorders, such as thyroid storm (remember thyroid involved in temperature/metabolism) or pheochromocytoma (tumour in adrenal glands) (bit like me at the moment !!); and miscellaneous events, including light anaesthesia, cocaine toxicity, or sepsis. ABG analysis ============ Acidosis The initial acid--base abnormality is **respiratory acidosis** due to increased carbon dioxide production. As ATP demand increases, further ATP generation is through glycolytic (glucose) means only. Glycolytic ATP production increases H+ production (Remember more Hydrogen means more acid) Once kidneys can't produce enough bicarbonate to buffer the excess H+, the PH falls leading to **metabolic acidosis**. The increased muscle metabolic activity increases lactate production. MH reaction can be associated with up to a sevenfold rise in the lactate concentration which may begin as early as 2 minutes after the start of exposure and the pH can reach values of 6.71 within 20 minutes. What happens after giving Sux??? ================================ MUSCLE FEATURES Masseter spasm The masseter muscle is a thick trapezoid-shaped muscle of mastication that originates from the zygomatic arch and inserts on the mandible. Masseter contraction jams the jaw to the maxilla and closes the mouth. Remember Sux is a **depolarizing** muscle relaxant which causes a sustained activation of postjunctional nicotinic acetylcholine receptors at the neuromuscular junction (sux is like a double dose of acetylcholine which causes fasciculations (Extra muscle contraction) and then stops muscle contraction for a couple of minutes, until the extra sux is metabolised). In patients susceptible to MH, succinylcholine-induced persistent depolarization leads to a sustained increase in intracellular calcium ions which leads to prolonged contraction (fasciculations). This masseter spasm usually resolves within 5 minutes even if no treatment is used. Masseter spasm that lasts more than 2 minutes and hinders endotracheal intubation is considered abnormal and is associated with a 24--50% likelihood of MH susceptibility. Generalised muscle rigidity =========================== A degree of skeletal muscle relaxation is required for most surgical procedures. Profound muscle relaxation is generally required for body cavity procedures, where spontaneous or reflex patient movement could be catastrophic, e.g., during neurosurgery, or to facilitate tracheal intubation. Neuromuscular blocking drugs, acting at the neuromuscular junction, paralyze the muscles to produce such profound relaxation. Generalised muscle rigidity might happen later, and the higher intracellular calcium ions may be triggered by volatile agents (gases). This happens later though and you may see hypercapnia (From tachycardia and rise in temperature) happen first. So it kind of shows signs of the inside first, then leads to rigidity (what you can see)-so its important to reverse quickly. Why Tachycardia?? ================= Think about the BP equation (preload/afterload/contractility + HR = cardiac output). Oxygen is a part of blood volume (i.e. Stroke volume)- so if this decreases (because of the rise in C02 then heart rate will increase to keep cardiac output stable. Plus HR also increases from hypercapnia (excessive use of ATP-energy which release stress hormones (catabolic) which eat up oxygen. The magnitude, rate, and time of increase in heart rate can be variable and depend on the individual and severity of the reaction. In some cases, a rise in heart rate may counteracted if the sympathetic response is obtruded, for example, in patients receiving beta-blockers or the potent opioid remifentanil. It must be noted that tachycardias very common in the perioperative period and is often related to sympathetic stimulation caused by noxious stimulation, such as by airway instrumentation, surgical stimulus, or volatile gases. The tachycardia observed under these circumstances usually resolves after the stimulus is removed. Any progressive increase in heart rate that is associated with hypercarbia should, however, raise a suspicion of MH. Rhabdomyolysis ============== - Rhabdomyolysis refers to the breakdown of skeletal muscle which causes leakage of myoglobin and potassium into extracellular blood. Inside the cell (Intracellular) potassium is usually 150 mmol/L Outside the cell (extracellular) potassium is usually 4.0 mmol/L So just imagine how much potassium is now leaking out and increasing!! As the MH reaction progresses, muscle cell death occurs leading to a more dramatic release of potassium into the blood and potentially life-threatening hyperkalaemia. TREATMENT OF MH =============== Dantrolene: Dantrolene depresses excitation-contraction coupling in skeletal muscle by binding to the ryanodine receptor 1 and decreasing intracellular calcium concentration. Remember, Ryanodine receptors mediate the release of calcium from the sarcoplasmic reticulum, an essential step in muscle contraction. Remember it is Ca++ which binds with Troponin (the one that's between actin and myosin), so if no cacium troponin stays put in place and doesn't allow actin and myosin to rub against each other-which is what causes the muscle contraction in the first place. Dantrolene is classified as a direct-acting skeletal muscle relaxant. It is currently the only specific and effective treatment for malignant hyperthermia. In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by affecting the contractile response of the muscle at a site beyond the myoneural junction. In skeletal muscle, Dantrium dissociates excitation-contraction coupling, probably by interfering with the release of Ca2+ from the sarcoplasmic reticulum. The Romantic story of Miss Actin & Mr Myosin ============================================ Where it all started (Normal physiology of skeletal muscle contraction) ----------------------------------------------------------------------- Mr C++ is the father of Troponin. Now Troponin was a man in LUST!! He had his eyes on Miss Actin. He would always keep himself in the middle of Miss Actin and Mr Myosin to prevent them from rubbing against each other. This moodled with their ability to get excited (contraction=heat) (They couldn't get heated up!!) Mr Ca++ was distraught with his child Troponin, so whenever the Ryanodine receptor (gateway) opened the doors and let in some acetyl choline (red-bull) he would bind himself to Troponin and move him from between poor Miss Actin & Mr Myosin and let them rub together-contract-and generate some heat together (muscle contraction=heat) Mr Ca++ got the advantage (Link to changes from MH) --------------------------------------------------- One day the doors (Ryonide receptors) to Miss Actin & Mr Myosins house were damaged (abnormality)-so this meant Mr Ca++ could bind to Troponin all the time and keep him out from between Miss Actin & Mr Myosin's way. This meant they were rubbing against each other all the time (excessive muscle contraction). But this wasn't good too, cos they were causing a lot of damage to their muscles (myoglobin), making too much noise (Hypercapnia)- interrupting others balance (releasing too much potassium) which was raising their heart rate (Tachycardia) and causing them to frown (acidosis). They were huffing and puffing-gasping for oxygen since they were losing sleep (using up ATP) which was making the feel unwell (C02 build up). This needed to Stop! (Dantrole-treatment) ----------------------------------------- It was clear that something needed to be done quick! Somebody decided to block the doors (Ryonide receptors) with an iron bar (DANTROLENE)- so Mr Ca++ couldn't get to Troponin- This meant that Troponin stayed merrily between Miss Actin & Mr Myosin and stopped them from rubbing against each other and this stopped them from contracting and generating heat. The End! -------- Key Words in a sequence: ======================== **Acetyl Choline**: Neurotransmitter for muscle contraction **Ryanodine Receptors**: gateway to release calcium **Calcium**: Positive Positive ion **Sarcoplasmic Reticulum**: Web like-surround tubular structure in muscle cell **Actin:** protein/ligament-like found in muscle tissue-rubs against Myosin for contraction **Troponin**: Regulatory protein important in skeletal and cardiac contraction **Myosin**: protein/ligament-like found in muscle tissue **Hypermetabolic**: When we are using too much ATP (energy) **Myoglobin**: We release in emergency damage to muscle cells- protein which contains iron and 02-is released during MH into the blood **Hypercatabolic**: Release of various hormones-like cortisol-cytokine (They consume 02 and make us tachycardic) **Rhabdomyolysis**: breakdown of skeletal muscle causing myoglobin and potassium leakage out of cell.